Epigenetic dynamics in normal and malignant B cells: die a hero or live to become a villain

Abstract

Normal B cell development, activation, and terminal differentiation depend on the intricate dynamics of cooperating epigenetic and non-coding components to control the level and timing of expression of thousands of genes. Recent genome-wide studies have integratively mapped changes in the chromatin landscape, DNA methylome, 3-dimensional interactome, and coding and non-coding transcriptomes of normal and malignant B cells. Genetic ablation in human cells and mouse models has begun to elucidate the coordinated roles of essential epigenetic modifiers, key transcription factors, and long non-coding RNAs in B cell biology. Perturbation of these stewards of the epigenome drive B cell oncogenesis, but may be exploited to develop new avenues of therapy.

Figure 1.. Epigenetic mechanisms regulating B cell activation and the GC reaction.

A) Simplified diagram shows the stages of peripheral B cell activation and maturation in the GC reaction. B) DNA hypomethylation leads to methylation heterogeneity during B cell maturation. As naïve B cells are activated and form GCs, i) increased histone acetylation and loss of repressive methylation drastically alter the chromatin landscape, which ii) decompacts chromatin and generates chromatin loops, iii) facilitating increased promoter-enhancer contacts and a massive increase in gene expression. D) lncRNA transcription at switch regions contributes to SHM and CSR through two mechanisms; i) R-loops -- DNA-RNA hybrid and ssDNA -- are formed during transcription and the ssDNA can be targeted by AID or ii) switch transcripts form G-quadruplexes that are bound by AICDA and unwound by DDX1 to facilitate R-loop formation at switch regions. SHM – somatic hypermutation; CSR – class-switch recombination; BCR – B cell receptor.

Figure 2.. Subversion of epigenetic mechanisms in B cell cancers.

A) Overview of the cell of origin for many B cell cancers. B) B cell lymphomas exhibit increased intra- and inter-sample DNA methylation heterogeneity due to i) aberrant hypomethylation at major transcription factor and AICDA binding sites, and ii) aberrant histone and DNA hypermethylation at gene promoters regulatory elements that may result in transcriptional repression. C) Frequencies of select mutations in epigenetic modifiers, chromatin remodelers, and histone proteins in several B cell cancers. ABC-DLBCL – Activated B-cell-like subtype of diffuse large B cell lymphoma; GCB-DLBCL – Germinal center B-cell-like subtype of diffuse large B cell lymphoma; U-CLL – unmutated chronic lymphocytic leukemia; M-CLL – mutated chronic lymphocytic leukemia; FL – Follicular lymphoma; MM – Multiple myeloma; BL - Burkitt lymphoma; MCL – Mantle cell lymphoma.

Figure 3.. The complex, synergistic interplay between genetic and epigenetic aberrations of the PVT1/MYC locus.

i) The MYC and PVT1 promoters exhibit competitive binding to a group of enhancers (orange bars) located within the PVT1 gene body. ii) Mutations to the PVT1 promoter eliminate its interaction with this regulatory cluster, allowing the MYC promoter to freely interact with the enhancers and increase MYC expression. iii) Independently, IgH promoter/enhancer translocations or amplifications of the locus can result in PVT1 overexpression, which binds to the MYC protein and prevents its degradation.